Eszopiclone, also known as (S)-zopiclone or (S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), is formulated as the free base and is sold as LUNESTA®. It is used to treat different types of sleep problems, such as difficulty in falling asleep, difficulty in maintaining sleep during the night, and waking up too early in the morning. Most people with insomnia have more than one of these problems. See, e.g., WO 93/10787; Brun, J. P., Pharm. Biochem. Behav. 29: 831 832 (1988). The compound eszopiclone and various methods of treatment are disclosed at least in the following U.S. Pat. Nos. 7,125,874; 6,864,257; 6,444,673; 6,319,926; and 5,786,357.
Racemic zopiclone, rac-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), also formulated as the free base, has been sold in Europe for many years to treat different types of sleep problems.
The active ingredient eszopiclone in its free base form has a very strong bitter taste. Human taste studies indicated that even a solution with very low concentration, e.g., 0.01 mg/mL, the bitter taste can be detected by the human tongue. Therefore, trace amounts of the active ingredient on the surface of the tablets, or any film coating defects leading to the direct exposure of the active ingredient on the surface of the tablets, or instantaneous dissolving tablets in human mouths would be detected owing to the extremely bitter taste when the patients swallow LUNESTA® tablets with water.
Many forms of analytical methods and apparatus have been proposed to measure or identify the active ingredient on the surface of the tablets. For instance, Raman mapping spectra were used to detect the active ingredient of alprazolam from the flattened surfaces of six alprazolam tablets (Sasic, Slobodan. Analytical R&D, Pfizer Global Research and Development, Sandwich, UK). Pharmaceutical Research (2007), 24(1), 58-65). Additionally, many analytical methods have been proposed to evaluate the film coating property of tablets. For example, the novel X-ray photoelectron spectroscopic (XPS) technique combined with principal component analysis of spectra-to-image datasets was employed to study the effects of atomization air pressure used during the coating process on film-tablet interfacial thickness (Barbash, Dmytro; Fulghum, Julia E.; Yang, Jing; Felton, Linda. Physical Electronics USA, Inc., Chanhassen, Minn., USA, Drug Development and Industrial Pharmacy (2009), 35(4), 480-486.) But none of these techniques are able to accurately determine very small amounts of material at very short time frames.
Human taste panel studies, such as the “Lick and Roll” testing method (a method involving direct collection of human saliva from the patients who take LUNESTA® tablets) is not only time-consuming, but also requires large and expensive clinical studies. Further, the conventional dissolution method is not capable of capturing the dissolution profiles of the tablets in the incipient stages of dissolution because sampling requires time intervals of five minutes or longer. On the other hand, methods such as conventional UV fiber optics and/or LC-UV methods, while rapid, are not sensitive enough to accurately quantify the trace amount of the active pharmaceutical ingredient at the ng/mL level. Therefore, there is a strong need to develop a new method which can overcome the drawbacks of the known methods or techniques in the art.